Glucagon receptor antagonists

Patent metadata

Field	Value
Publication number	US-12208071-B2
Application number	US-201916969521-A
Country	US
Kind code	B2
Filing date	Feb 13, 2019
Priority date	Feb 13, 2018
Publication date	Jan 28, 2025
Grant date	Jan 28, 2025

Abstract

Provided herein are solid state forms of compounds, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or co-crystals and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity. Further, provided herein are pharmaceutical compositions and methods of treating, preventing, ameliorating, delaying the time to onset or reducing the risk for the development or progression of at least one condition, disease, or disorder for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance, hyperglycemia, ketoacidosis, or ketosis.

First claim

What is claimed is:

1. A crystalline form of sodium (R)-2-(4-(2-(4′-(tert-butyl)-[1,l′-biphenyl]-4-yl)-3-oxo-3-((2′,4′,6′-trimethyl-[1,1′-biphenyl]-4-yl)amino) propyl)benzamido) ethane-1-sulfonate characterized as Form A,
wherein Form A is characterized by three or more peaks in an X-ray powder diffraction pattern, wherein the three or more peaks are selected from the group consisting of a peak at 4.7±0.2 degrees, a peak at 7.0±0.2 degrees, a peak at 9.3 degrees, a peak at 11.0±0.2 degrees, a peak at 11.4±0.2 degrees, a peak at ±0.2 11.9 degrees, a peak at 13.8±0.2 degrees, a peak at 21.4±0.2 degrees, and a peak at 23.8±0.2 degrees, when measured at room temperature with monochromatic Kα1 radiation.

2. The crystalline form of claim 1 , wherein Form A is characterized by a peak at 4.7 degrees, a peak at 7.0±0.2 degrees, a peak at 9.3±0.2 degrees, a peak at 11.0±0.2 degrees, a peak at 11.4±0.2 degrees, a peak at 11.9±0.2 degrees, a peak at 13.8±0.2 degrees, a peak at 21.4±0.2 degrees, and a peak at 23.8±0.2 degrees in an X-ray powder diffraction pattern, when measured at room temperature with monochromatic Kα1 radiation.

3. The crystalline form of claim 1 , wherein Form A is characterized by an X-ray powder diffraction pattern of FIG. 1 .

4. The crystalline form of claim 1 , wherein Form A is characterized by a DSC thermogram of FIG. 29 .

5. The crystalline form of claim 1 , wherein Form A is characterized by a purity of at least about 99.0%.

6. The crystalline form of claim 1 , wherein Form A is characterized by the presence of no more than about 0.08% of impurity A, no more than about 0.12% of impurity B and no more than about 0.05% of impurity C.

7. The crystalline form of claim 1 , wherein Form A is characterized by at least one of a D 10 of about 4.39 μm, a D 50 of about 16.10 μm, and a D 90 of about 43.18 μm.

8. The crystalline form of claim 1 , comprising the following compound of Formula II:

9. A pharmaceutical composition comprising the crystalline form of claim 1 in combination with one or more pharmaceutically acceptable diluents or carriers.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition further comprises a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of insulin sensitizers, biguanides, metformin, PPAR agonists, triglitazone, pioglitazone, rosiglitazone, insulin and insulin mimetics, somatostatin, α-glucosidase inhibitors, voglibose, miglitol, acarbose, dipeptidyl peptidase-4 inhibitors, SGLT-2 inhibitors, liver X receptor modulators, insulin secretagogues, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, sulfonylureas, tolazamide, tolbutamide, tolcyclamide, nateglinide, repaglinide, other glucagon receptor antagonists, GLP-1, GLP-1 mimetics, exenatide, liraglutide, DPPIV inhibitors, GLP-1 receptor agonists, GIP, GIP mimetics, GIP receptor agonists, PACAP, PACAP mimetics, PACAP receptor 3 agonists, cholesterol lowering agents, HMG-COA reductase inhibitors, statins, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, rivastatin, NK-104, itavastatin, nisvastatin, nisbastatin, ZD-4522 rosuvastatin, atavastatin, visastatin, a cholesterol absorption inhibitor ezetimibe, sequestrants, nicotinyl alcohol, nicotinic acid and salts thereof, PPAR α agonists, PPAR α/γ dual agonists, inhibitors of cholesterol absorption, acyl CoA: cholesterol acyltransferase inhibitors, anti-oxidants, PPAR δ agonists, antiobesity compounds, ileal bile acid transporter inhibitors, anti-inflammatory agents, and protein tyrosine phosphatase-1B (PTP-1B) inhibitors.

11. A method of treating, or ameliorating a condition, disorder, or disease responsive to the modulation of a glucagon receptor, or one or more symptoms thereof, comprising administering a therapeutically effective amount of the crystalline form of claim 1 to a subject in need thereof.

12. A method of treating, or ameliorating a condition, disorder, or disease responsive to the modulation of a glucagon receptor, or one or more symptoms thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a subject in need thereof.

13. A method of treating, or ameliorating a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level, or one or more symptoms thereof, comprising administering a therapeutically effective amount of the crystalline form of claim 1 to a subject in need thereof.

14. A method of treating, or ameliorating a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level, or one or more symptoms thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a subject in need thereof.

15. A method of treating, or ameliorating at least one condition, disorder, or disease, or one or more symptoms thereof, selected from the group consisting of type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, ketosis, nonketotic hyperosmolar coma, nonketotic hyperglycemia, impaired glucose tolerance (IGT), insulin resistance syndromes, syndrome X, low HDL levels, high LDL levels, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, accelerated gluconeogenesis, excessive or greater than normal levels of hepatic glucose output, and lipid disorders, comprising administering a therapeutically effective amount of the crystalline form of claim 1 to a subject in need thereof.

16. A method of treating, or ameliorating at least one condition, disorder, or disease, or one or more symptoms thereof, selected from the group consisting of type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, ketosis, nonketotic hyperosmolar coma, nonketotic hyperglycemia, impaired glucose tolerance (IGT), insulin resistance syndromes, syndrome X, low HDL levels, high LDL levels, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, accelerated gluconeogenesis, excessive or greater than normal levels of hepatic glucose output, and lipid disorders, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a subject in need thereof.

17. The method of claim 11 , wherein the condition, disorder, or disease is diabetes.

18. The method of claim 11 , wherein the condition, disorder, or disease is ketoacidosis.

19. The method of claim 11 , wherein the subject is a mammal.

20. The method of claim 11 , wherein the subject is human.

Assignees

• Ligand Pharm Inc

Inventors

• Zhi Lin
• Henderson Ian
• Kaloko Joseph
• Osterhout Martin

Classifications

• C07C315/06

  Separation; Purification; Stabilisation; Use of additives · CPC title

• C07C315/04

  by reactions not involving the formation of sulfone or sulfoxide groups · CPC title

• C07C309/24

  of a carbon skeleton containing six-membered aromatic rings · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title